With the development of more and more types of extracted, synthetic or genetically engineered hormone-like substances which are effective at very low levels of concentration, the need for implantable or ingestable controlled-release capsules has grown considerably and many designs for such devices have been proposed. One convenient form of implantable device is an open-ended cylinder or tube of a few millimeters in diameter (so that it can be implanted by the use of a hypodermic syringe) formed from material which is biocompatible but generally impervious to body fluids.
If the sustained release of a single drug dose is desired, the drug is simply mixed with a suitable excipient, loaded into the device and implanted. Whereupon, the action of the body fluids gradually dissolves, disperses or penetrates the excipient and releases the drug over a period of time. If pulsatory delivery is required, the capsule cylinder may be loaded with a succession or `stack` of alternating `active` and `spacer` layers each comprising a suitable excipient, carrier or matrix. Each active layer contains a dose, or a relatively high concentration of the drug(s) to be delivered, while each spacer layer contains no drug(s) or a relatively low concentration thereof. Dissolution, leaching or erosion of each successive layer (by body fluids after implantation) provides the desired pulsatory drug delivery, while the formulation of the excipient of an active layer determines the profile of the corresponding dose, and the formulation of a spacer layer determines the time interval between the doses of the adjacent active layers.
Such known capsules may be divided into those which are `active` (or `swellable agent`) and those which are `passive` (or `un-swellable agent`). In the latter, the timing and rate of release of the drug doses represented by the active layer(s) depends upon the formulation of the excipient(s) and drug(s) employed, given a particular composition of surrounding body fluid. In the former, the layer-stack is pushed or extruded gradually from the open end of the capsule by a `swellable agent` located at the other--and closed--end of the capsule, so that one layer after another is ejected for dissolution into the body fluids. Thus, the interval between doses--and to some degree, the dose profile as well--is determined by the rate of extrusion as well as the excipient formulation.
A basic form of pulsatory passive capsule is disclosed by U.S. Pat. No. 5,011,692 to Sumitomo. Here a hollow cylindrical casing of impermeable material contains a stack of alternating active and spacer layers in which the excipient is formed by a specially formulated bio-compatible polymer which can be leached or eroded by body fluids. The problem with such a design is that the dose profile and timing of the first layers tends to be quite different to those of the last layers due to the reduced diffusion-rates in a near-empty capsule. The problem is accentuated where long, thin multi-dose capsules are employed. To compensate, the formulation of the layers may be graded along the stack--but at the penalty of greatly increased manufacturing cost. Also, since the innermost layers of such a stack are likely to be highly permeable, the drug in those layers is likely to diffuse from one to another during storage thereby degrading the desired release profile.
An alternative form of passive capsule (e.g. WO9217165 in the name of the Victorian Pharmacy College) involves the encapsulation of a drug-excipient mixture with an erodable (but initially) impervious coating which gradually degrades in vivo to release the drug. But such an approach is notoriously non-linear unless the distribution of the drug within the excipient is carefully graded or many micro-capsules with different coatings are separately implanted or included in the one implanted macro-capsule.
Another form of passive capsule (exemplified by United Kingdom patent 2,241,485 to NRDC and U.S. Pat. No. 5,137,727 to Alza) uses a casing having one or more chambers connected in series with one another and to the external environment by apertures which are stopped with bioerodable plugs, each chamber containing a separate dose of the drug to be delivered. Reliance is thus placed upon the characteristics of the plug(s) to ensuring the desired timing of the dose(s), while the profile of the dose itself is--as before--determined by the formulation of its excipient and the drug. However, the release profile of the doses in the inner chamber will differ even more radically from those in the outer chambers than is the case with a layered-stack capsule.
In another form of chambered passive capsule, (e.g. NRDC United Kingdom patent 2,243,777) the connection between a single drug-containing chamber and the surrounding fluid of the body is restricted by the tube, the outer end of which is closed with a soluble plug. Such a capsule may be satisfactory where the delayed release of a sustained single dose is required, but its design obviously not suited to pulsatory delivery.
An alternative approach to the linearity problem is to employ a capsule casing which is formulated so that it erodes away only at the edge--that is, at the open end--to gradually successive expose active and spacer layers of the stack. However, the formulation of a casing of this type is extremely difficult and, to the applicant's knowledge, has not been achieved with practical success.
The active or pump capsule avoids the inherent linearity problem of the passive capsule by gradually pushing the layer-stack out of the open end of the capsule so that each successive layer becomes the top or outermost layer thereby ensuring that its release profile is essentially the same as that of the previous (and now dissolved or dispersed) layers. Also, in this way, the timing of the release of each dose is now determined largely by rate of extrusion (i.e. by the swellable agent design) rather than solely by the formulation and thickness if the spacer layer(s). The pump may be physical (e.g. driven mechanically, electro-mechanically or by gas pressure), physio-chemical (e.g. driven by an expanding hydrogel which imbibes fluid from the environment) or osmotic (e.g. driven by an expanding solute which imbibes a solvent--usually water--from the environment through an ion-selective membrane). The latter two forms of pump are preferred because of their relatively low cost and small size, because they generate a more uniform force over their stroke (in comparison with most spring or gas-operated swellable agents) and because their materials can be more readily made biocompatible. A range of osmotic pumps for this purpose are disclosed in U.S. Pat. Nos. 4,203,440, 4,203,441 and 4,203,442 to Alza.
The active devices of the prior art are designed to provide a constant rate of extrusion with the gradual diminution of swellable agent pressure being offset by the lowered friction of a shorter stack as delivery progresses. This allows the timing of the dose(s) to be made proportional to the thickness of the corresponding layer(s). This problem is said to be addressed by Merck in its Australian patent application 73310/87 where it is proposed that the spacer layers of a multi-dose active capsule should employ an expanding excipient formulation. While it is suggested the effective length of the capsule is made much greater than its physical length in this way, a little thought will show that the inclusion of expanding spacer layers must have the effect of increasing the average extrusion rate of material from the capsule, thus effectively shortening its effective length (compared to an equivalent capsule with non-expanding layers).